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Aldehydes & Chapter 21 Nomenclature of

• If the CHO is bonded to a chain of , find the longest chain containing the CHO group, and change the –e ending of the parent to the suffix –al. • If the CHO group is bonded to a ring, name the ring and add the suffix –carbaldehyde. • Number the chain or ring to put the CHO group at C1, but omit this number from the name. • Apply all the other usual rules of nomenclature. Common Names of Aldehydes

• Like carboxylic acids, many simple aldehydes have common names that are widely used. • A common name for an is formed by taking the common parent name and adding the suffix –aldehyde.

• Greek letters are used to designate the location of substituents in common names. Nomenclature of Ketones

• In the IUPAC system, all ketones are identified by the suffix “one”.

• Find the longest continuous chain containing the , and change the –e ending of the parent alkane to the suffix -one.

• Number the chain to give the carbonyl carbon the lowest number.

• Apply all of the usual rules of nomenclature.

• With cyclic ketones, numbering always begins at the carbonyl carbon, but the “1” is usually omitted from the name.

• The ring is then numbered clockwise or counterclockwise to give the first substituent the lower number. Common Names of Ketones

• Most common names for ketones are formed by naming both groups on the carbonyl carbon, arranging them alphabetically, and adding the word “”.

• Three widely used common names for some simple ketones do not follow this convention: Naming Ketones and Acyl Groups

• Sometimes, acyl groups must be named as substituents. • The three most common acyl groups are shown below: Naming Enals and Enones

• Compounds containing both a C-C and an aldehyde are named as enals. • Compounds that contain both a C-C double bond and a ketone are named as enones. • The chain is numbered to give the carbonyl the lower number. Interesting Aldehydes and Ketones—Formaldehyde

• Billions of pounds of formaldehyde are produced annually by the oxidation of methanol. • It is sold as a 37% aqueous solution called formalin which is used as a disinfectant, antiseptic, and preservative for biological specimens. • It is a product of incomplete combustion of coal, and is partly responsible for the irritation caused by smoggy air. Interesting Aldehydes and Ketones—Acetone

• Acetone is an industrial solvent. • It is also produced in vivo during breakdown of fatty acids. • Diabetics often have unusually high levels of acetone in their blood streams. • Thus, its characteristic odor can be detected on the breath of diabetic patients when the disease is poorly controlled. Natural Aldehydes and Ketones with Strong Odors Steroids with Carbonyls

• Many steroid hormones contain a carbonyl along with other functional groups. • Cortisone and prednisone are two anti-inflammatory steroids with closely related structures. • Cortisone is secreted by the body’s adrenal gland, whereas prednisone is the synthetic analogue and is used as an anti-inflammatory for asthma and arthritis. Preparation of Aldehydes Preparation of Ketones Oxidative Cleavage of

• Aldehydes and ketones are also both obtained as products of the oxidative cleavage of alkenes. General Reactions of Aldehydes and Ketones

[1] Reaction at the carbonyl carbon—the elements of H and Nu are added to the carbonyl group.

[2] Reaction at the α carbon. (basic or neutral)

• In this process, nucleophilic attack precedes protonation. • This mechanism occurs with negatively charged or strong neutral nucleophiles.

• LiAlH4, NaBH4, Grignard and Alkyl Lithium Reagents are all examples of basic nucleophilic addition. Acid-Catalyzed Nucleophilic Addition

• In this mechanism, protonation precedes nucleophilic attack as shown above. • With some neutral nucleophiles, nucleophilic addition only occurs if an acid is present to activate the carbonyl by protonation. • Acid-catalyzed hydration of an aldehyde – part of the Cr (VI) oxidation of an aldehyde to a – is an example. Acid-Catalyzed Nucleophilic Addition

• The effect of protonation is to convert a neutral carbonyl group to one having a net positive charge. • This protonated carbonyl is much more electrophilic and susceptible to attack by a nucleophile. Good Nucleophiles

• Nucleophilic trends in carbonyl attack are not the same as in straightforward substitution reactions at sp3 carbon atoms. • Cl¯, Br¯, and I¯ are good nucleophiles in substitution reactions at sp3 hybridized carbons, but they are ineffective nucleophiles in addition. • When these nucleophiles add to the sp2 carbonyl carbon, they cleave the C–O π bond, forming an alkoxide. • Since X¯ is a much weaker base than the alkoxide formed, equilibrium favors the starting materials, not the addition product. Effective Nucleophiles in Nucleophilic Addition

• Other nucleophiles add to carbonyl groups to form unstable intermediates which rapidly undergo elimination. • This addition–elimination process, particularly with -related nucleophiles, replaces a C=O with a C=N.

• For example, (RNH2) add to carbonyl groups in the presence of mild acid to form unstable carbinolamines, which readily lose water to form imines.

• In cases in which the initial addition adduct is unstable, it is enclosed within brackets, followed by the final product. Nucleophilic Addition Reactions Wittig Reaction

• The Wittig reaction uses a carbon nucleophile (the Wittig reagent) to form alkenes—the carbonyl group is converted to a C=C. Wittig Reagents • The Wittig reagent is an organophosphorus reagent. • A typical Wittig reagent has a phosphorus atom bonded to three phenyl groups, plus another alkyl group that bears a negative charge. • A Wittig reagent is an , a species that contains two oppositely charged atoms bonded to each other, with both atoms having octets. • Phosphorus are also called phosphoranes. Synthesis of the Wittig Reagent & the Wittig Reaction

• Mechanism for the 2nd Example will be provided on the board: 1) The formation of the Wittig reagent from triphenylphospine. 2) Reaction of the ylide with the carbonyl to form the . Use of the Wittig Reaction • One limitation of the Wittig reaction is that a mixture of stereoisomers sometimes forms.

• The Wittig reaction has been used to synthesize many natural products.

Figure 21.8 A Wittig reaction used to synthesize β-carotene The Wittig Reaction Leads to Precise Placement of the Double Bond • An advantage of the Wittig reaction over elimination methods used to synthesize alkenes is that the Wittig reaction always gives a single constitutional isomer. • Consider the two methods that can be used to convert cyclohexanone into cycloalkene B.

• followed by dehydration:

• Using the Wittig reaction to achieve the same synthesis gives only the desired compound. Retrosynthetic Analysis of Wittig Reactions

• Suggest a synthesis of the following compound from an appropriate ketone or aldehyde and an alkyl halide via a Wittig Reaction. Formation of Imines • Amines are classified as 1°, 2°, or 3° by the number of alkyl groups bonded to the nitrogen atom.

• Treatment of an aldehyde or a ketone with a 1° amine affords an imine (also called a ).

32 Imine Properties • Because the N atom of an imine is surrounded by three groups (two atoms and a lone pair), it is sp2 hybridized, making the C–N– R bond angle 120°, (not 180°). • Imine formation is fastest when the reaction medium is weakly acidic (pH 4–5).

• Mechanism of Imene formation: Role of Acidity in Imine Formation

• In imine formation, mild acid is needed for protonation of the to form a good leaving group. • Under strongly acidic conditions, the reaction rate decreases because the amine nucleophile is protonated. • With no free electron pair, it is no longer a nucleophile, and so nucleophilic addition cannot occur. Imines in Nature

• Many imines play vital roles in biological systems. • A key molecule in the chemistry of vision is the highly conjugated imine rhodopsin, which is synthesized by the rod cells of the eye from 11-cis- retinal and a 1° amine in the protein opsin. The Key Reaction in the Chemistry of Vision Formation of

• A 2° amine reacts with an aldehyde or ketone to give an . • Enamines have a nitrogen atom bonded to a C–C double bond. Formation of Imines vs. Enamines

• With a 1o amine, the intermediate ion still has a proton on the N atom that may be removed to form a C=N.

• With a 2o amine, the intermediate iminium ion has no proton on the N atom.

• A proton must be removed from an adjacent C–H bond, and this forms a C=C. of Imines and Enamines

• Because imines and enamines are formed by a reversible set of reactions, both can be converted back to carbonyl compounds by hydrolysis with mild acid. • The mechanism of hydrolysis is the exact reverse of the mechanism written for formation of imines and enamines.